Topical compositions for reducing the effects of aging

ABSTRACT

The present invention comprises ternary compositions of tamibarotene and/or ammonium lactate in Pemulen for treatment of effects of aging.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/380,808, filed Apr. 10, 2019, which is a continuation of U.S. patentapplication Ser. No. 14/775,920, filed Sep. 14, 2015, which is a U.S.National Stage patent application under 35 U.S.C. § 371 of InternationalPatent Application No. PCT/US2014/030033, filed Mar. 15, 2014, whichclaims benefit under 35 USC § 119(e) of U.S. Provisional PatentApplication No. 61/790,370, filed Mar. 15, 2013, and to U.S. ProvisionalPatent Application No. 61/789,701, filed Mar. 15, 2013, the contents ofwhich are incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

The present invention relates to novel cosmetic, and pharmaceuticalcompositions containing tamibarotene or ammonium lactate for topicalapplication in the treatment of wrinkles and dry skin.

Cosmetic preparations are widely used to improve looks or the way aperson feels about themselves. To be successful products must delivervisible results without side effects and should appear natural. Variousretinoids are known for their antiaging properties

Tamibarotene is a new synthetic retinoid drug recently approved forrelapsed or refractory acute promyelocytic leukemia (APL) in Japan. Itis a specific agonist for retinoic acid receptor alpha/beta.

Tamibarotene is orally active and was developed to overcome all-transretinoic acid (ATRA) resistance, with potential antineoplastic activity.

Compared to all-trans retinoic acid (ATRA), a natural retinoid indicatedfor a first-line treatment of APL, tamibarotene is chemically morestable and several times more potent as an inducer of differentiation inpromyelocytic leukemia cells. In contrast to ATRA, whose plasmaconcentration declines considerably during daily administration,tamibarotene sustains plasma level probably due to a lower affinity forcellular retinoic acid binding protein. Furthermore, adverse sideeffects were milder than those of ATRA in clinical trials. Miwako I,Kagechika H R&R Inc., Tokyo, Japan. Drugs of Today (Barcelona, Spain:1998) [2007, 43(8):563-568]. The structure of tamibarotene is shownbelow.

Tamibarotene

-   CAS No.: 94497-51-5-   Name: Benzoic acid,    4-[[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino]carbonyl]--   Superlist Name: Tamibarotene-   Formula: C22H25NO3-   Synonyms:    4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl)-2-naphthalenyl)carbamoyl]benzoicacid;N-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl)-2-naphthyl)terephthalamic    acid;Am 80 (pharmaceutical);Amnolake;NSC 608000;Retinoid. AM 80;-   Molecular Weight: 351.44

Tamibarotene may be synthesized as follows:

Formulation of cosmetics is well known in the art, United Statespublished patent publication number 20110059892 to Phillippe Moussouprovides examples of excipients widely use in cosmetic products.

Formulation of retinoids for topical delivery is problematic in that theformulations are unstable and rapidly degrade.

Ammonium lactate is a moisturizing agent known in the art that istypically formulated as an oil in water emulsion for topicaladministration. Currently available products suffer from the problemthat sufactants used to emulsify sunscreen agents also remove the agentsused to promote absorption from the skin when in the presence of water.This causes loss of UV absorbent activity and sun protectant effectssunscreen agents is lost.

The present ammonium lactate formulation solves the problem by using anew emulsification technology based on Pemulen. This invention providesnovel cosmetic combination compositions of ammonium lactatehttp://www.drugs.com/ingredient/ammonium, in a novel polymericemulsification technology using Acrylates/C10-30 Alkyl AcrylateCrosspolymer, (Pemulen™ TR-1 Polymeric Emulsifier). The Acrylates/C10-30Alkyl Acrylate Crosspolymer, is a versatile polymer which can emulsifyup to 30% oil by weight, within a pH range of 4-5.5, and up to 20% oilover the pH range of 3-11. Oil-in-water creams typically at 0.1 percentmethyl and propyl parabens are used at levels ranging from 0.01 to 0.3%and fragrance in an ternary sterically stabilized emulsion for topicalimprovement of skin appearance in normal and aged human skin. Like otheroil in water cosmetic emulsions, creams have traditionally beenemulsified with stearate or nonionic surfactants at 2%-6%. Inherent tosurfactant emulsification of UV absorbers is the propensity for thesurfactants to remove the absorbers from the skin when contacted

DESCRIPTION OF THE INVENTION Tamibarotene Compositions

This invention provides novel topical cosmeceutical combinations ofcompositions of tamibarotene, a natural and synthetic phytochemical andsalts with ammonium lactate, bisabalol, polyvinyl pyrrolidone (PVP K15to K90) for improvement of skin appearance in normal and aged humanskin.

The present formulations are stable for tamibarotene and the formulationitself.

In one embodiment the tamibarotne is dissolved in a polyethylene glycol(PEG) such as PEG 300 which is liquid at room temperature.

In another embodiment the formulation comprises a compositions which iswaxy at room temperature such as polyethylene glycol 1540.

In some embodiments the formulation also contains light mineral oil,glyceryl stearate, PEG-100 stearate, propylene glycol, polyoxyl 40stearate, glycerin, magnesium aluminum silicate, laureth-4, cetylalcohol, methyl and propyl parabens, methylcellulose, fragrance andwater.

In other embodiments tamibarotene is formulated with 0.05-15 percentlactic acid neutralized with ammonium hydroxide, as ammonium lactate toprovide a lotion pH of 4.0-6.0 suitable for use on the skin.

In another embodiment the formulation further comprises an anti-irritantsuch as bisabalol.

In another embodiment, sunscreens may be part of the formulation.

In yet another embodiment the formulation comprises antioxidants such asbutylated hydroxytoluene (“BHT”) or vitamin E. BHT in higherconcentrations may convey antiviral properties to the formulationsherein.

Tamibarotene and salts thereof, can be combined in binary and ternarycomposition with other phytochemical cosmetic anti-aging agents such asRosmarinus officinalis, specifically carnosic acid, Vitis vinifera(grape seed extract), specifically V. vinifera contains many phenoliccompounds. Anthocyanins can be found in the skin of the berries,hydroxycinnamic acids in the pulp and condensed tannins of theproanthocyanidins type in the seeds. Stilbenoids can be found in theskin and in wood.

It can also be formulated with Citronellol, limonene, fruit acids,Oenothera biennis (evening primrose oil, which is used for skindisorders such as eczema, psoriasis, and acne).

Glycyrrhiza glabra (licorice extract), Aframomum angustifolium seedextract, Diosgenin (wild yam), N6 furfuryladenine(kinetin), andErgothioneine. These treatments are particularly effective on personsafflicted by stress induced lines and wrinkles and reduction of acnelesions and to improve skin texture and skin color without an increasein puffiness

Application of tamibarotene (0.05 to 15 percent) alone or in acomposition containing bisabalol, an anti-irritant on a daily basis iseffective to reduce deep wrinkles.

EXAMPLE 1 Tamibarotene Gel

Method of Preparation

-   1. Calculate the required quantity of 0.05-15 percent of    Tamibarotene (Molecular weight ˜450), and then calculate each    ingredient for the total amount to be prepared 500 g.-   2. Accurately weigh/measure each ingredient.-   3. Dissolve the Tamibarotene and the butylated hydroxytoluene (BHT)    in the polyethylene glycol 300.-   4. Melt polyethylene glycol 1540 at about 55 C.-   5. Add the Tamibarotene and BHT solution to the melted base, mix    well and allow to cool.-   6. Package and label.

EXAMPLE 2 Methods of Use

Application of tamibarotene (0.05 to 15 percent) formulated as inExample 1 topically to the skin enhances the skin image and reduce thewrinkles for a period from about 8 to about 14 hours.

One of skill in the art will appreciate that considerable deviation fromthe teachings herein are permissible without departing from the spiritof the invention.

EXAMPLE 3 Ternary Anti-Wrinkle Emulsion of Tamibarotene

Currently available cosmetic products suffer from the problem thatsufactants used to emulsify sunscreen agents also remove the agents usedto promote absorption from the skin when in the presence of water. Thiscauses loss of UV absorbent activity and sun protectant effectssunscreen agents is lost.

An embodiment of the present invention solves the problem by using a newemulsification technology based on Pemulen. This invention providesnovel cosmetic combination compositions of ammonium lactatehttp://www.drugs.com/ingredient/ammonium-(1), in a novel polymericemulsification technology using Acrylates/C10-30 Alkyl AcrylateCrosspolymer, (Pemulen™ TR-1 Polymeric Emulsifier). The Acrylates/C10-30Alkyl Acrylate Crosspolymer, is a versatile polymer which can emulsifyup to 30% oil by weight, within a pH range of 4-5.5, and up to 20% oilover the pH range of 3-11. Oil-in-water creams typically at 0.1 percentmethyl and propyl parabens are used at levels ranging from 0.01 to 0.3%and fragrance in an ternary sterically stabilized emulsion for topicalimprovement of skin appearance in normal and aged human skin. Like otheroil in water cosmetic emulsions, creams have traditionally beenemulsified with stearate or nonionic surfactants at 2%-6%. Inherent tosurfactant emulsification of UV absorbers is the propensity for thesurfactants to remove the absorbers from the skin when contacted bywater.

Pemulen TR1 is a polymeric emulsifier produced by Noveon. A blockcopolymer consisting of a poly acrylic acid similar to the Carbopolresins presently used to make aqueous and solvent gels in artconservation (Carbopol 934, Carbopol 940, Carbopol 941) cross-linkedwith a long-chained methacrylate, this carbomer has a lipohipllicregions (the methacrylate) as well as hydrophilic regions (the acrylicacid). In the cosmetic industry literature, Pemulen TR-1 is part of aclass of copolymers arc referred to as acrylate/C10-30 alkyl acrylatecross polymers (6), having the following structure: Seehttp://pemulentr2.pbworks.com/f/PemulenTR2.pdf

These regions of differing affinity allow Pemulen TR1 or TR2 to act as aprimary emulsifier, that is, it can be used to make oil in wateremulsions without the usual required addition of soap or surfactant.

Pemulen TR1 or TR2 does not form emulsions in the same way thattraditional surfactants do. To produce oil in water emulsion, atraditional surfactant surrounds a droplet of oil to keep it suspendedin oil. Nonionic surfactants used for cleaning painted surfaces, asdescribed in Wolvers' Cleaning Painted Surfaces Aqueous Methods, mightbe used in concentrations as high as 30% to form a macroemulsion.

In contrast, Pemulen TR1 is said to form stable O/W emulsions with aslittle as 0.4%, binding to the oil droplets with the lipophilic portionsof the polymer chain that forms the gel.

Gels made with Pemulen TR-1 are most viscous in the pH range of 5-9. Arange of alkaline materials are suggested by the manufacturer toformulate aqueous gels using Pemulen TR-1, including sodium hydroxide,ammonium hydroxide, triethanolamine (TEA), and Ethameen C-25.

One interesting feature possessed by Pemulen is that this emulsifyingagent is designed to break when the gel is in contact with a saltconcentration similar to what one would find on human skin. This is adesirable in the cosmetics industry where moisturizers need to bequickly delivered and absorbed into the user's skin, but this may be aless desirable characteristic of an emulsion designed to clean works ofart. In practice, this breakage of the emulsion has been observed whenattempting to clean very grimy areas and allowing the gel to dwell foran extended period. Although the vast majority of cream or emulsionproducts in the marketplace contain water-insoluble actives, thesurfactants can re-emulsify the actives and cause wash-off, leaving theskin unprotected.

Those familiar with the art have countered this phenomenon byincorporating waxes or water resistant, film-forming polymers into theirformulations. Such a polymer forms an effective barrier, which preventsabsorber wash-off, but it may produce negative aesthetic effects such aslong rub-in times and a tacky or heavy feel on the skin. However, anovel combination of tamibarotene and Pemulen® polymeric emulsifiersmeet the FDA definition of “water-proof” without the use of film-formingpolymers, waxes and the like. Because these emulsions contain verylittle or no surfactants, the water-insoluble UV absorbers remain on theskin, even after an 80 minute exposure to water. The triggered releaseof the oil phase upon product application ensures that the absorbers arefree to spread onto the epidermis where they are immediately active.

This invention specially formulates tamibarotene to provide a cream pHof 4.5-6.5. It may also contain glycerin, isopropyl palmitate,dimethicone, ginko biloba, methyl paraben, propyl paraben or butylparabens fragrance and water.

In one embodiment Tamibarotene is present from about 0.05-15 percent.Optionally, the formulation comprises alpha-Bisabolol, an anti-irritant,and/or a retinoid, such as Tamibarotene. or a triterpinoid such asBetulen [473-98-3] C30H50O2, molecular mass 442,7 and related compoundslike betulin, lupeol, and betulinic acid.

The formula is a ternary formulation consisting of three parts which areultimately combined to form a stable oil in water emulsion. The order ofaddition of the ingredients should be followed strictly as written.Otherwise, the ingredients fall out of solution.

TABLE 2 Ingredient Percent Weight (g) Ternary Ingredient-Part 1 Order ofAddition Demineralized Water  63.1 155.5 Methyl Paraben  0.1  0.5 PropylParaben  0.1  0.5 Glycerin  2.0  10.0 Tamibarotene (20 wt. %)  8.0 200.0Total  73.3 366.5 Ternary Ingredient-Part 2 Order of AdditionDemineralized Water  18.0  90.0 Isopropyl Palmitate  2.5  12.5Dimethicone (Mw 30,000)  2.5  12.5 White Petrolatum  1.0  5.0 Ginkgo(Ginkgo biloba)  1.0  5.0 Total  25.0 125.0 Ternary Ingredients-Part 3Order of Addition Pemulen ® TR  1.5  7.5 Fragrance (Belle Air #7564) 0.2  1.0 Total  1.7  8.5 Total all 3 parts 100.0 500.0

A. Part 1.

Part 1 is formed as follows:

-   -   a. Add Demineralized water to a 1000 ml beaker. Stirring or        Agitation at 600 rpm    -   b. Add methyl paraben    -   c. Add propyl paraben    -   d. Add glycerin    -   e. Add Tamibarotene    -   f. Increase stirring rate or agitation to 1500 rpm

B. Part 2

Part 2 is formed as follows:

-   -   a. Add demineralized water to an 800 ml beaker. Stir or        Agitation at 600 rpm    -   b. Add isopropyl palmitate    -   c. Add dimethicone    -   d. Add white petrolatum    -   e. Add gingko biloba    -   f. Increase agitation or stirring 1500 rpm

Mix part 1 and part 2 for 30 minutes

-   -   a. Slow agitation or stirring down on part 1 to 600 rpm and        blend part 2 into part 1    -   b. Increase agitation of the combined formulation to 1800 rpm        for 30 minutes.

C. Part 3

The final formulation is produced as follows:

-   -   a. Slow agitation of combined formulation to 600 rpm    -   b. Add Pemulen® TR1 OR TR2 very slowly (all of it)    -   c. Increase stirring speed to 1800 rpm for 30 minutes to        disperse all of Pemulen® TR1 OR TR2    -   d. Increase agitation to 2800 rpm and hold until the emulsion is        smooth and creamy without any of the oils floating on the        surface.    -   e. Slow agitation down to 600 rpm and add the fragrance    -   f. Mix well and place in a proper container (jar or tubes).

EXAMPLE 4 Tamibarotene Cream

A tamibarotene cream was prepared by conventional methods according tothe following formulation (data in % by weight) in Table 3.

TABLE 3 % by Phase Ingredients INCI name weight A Water Aqua 67.10Glycerol Glycerin  5.00 Preservatives q.s. B Crodafos CES CetearylAlcohol (and) Dicetyl  5.00 Phosphate (and) Ceteth-10 Phosphate Myritol331 Coco Glyceride  6.00 Tegosoft TN C12-15 Alkyl Benzoate  3.00Tegosoft DC Decyl Cocoate  3.00 Fitoderme Squalane  2.00 C NaOH solutionSodium Hydroxide q.s. D Dow Corning 345 Cyclomethicone  3.00 AristoflexAVC Ammonium  0.40 Acryloyldimethyltaurate/ VP Copolymer E EDG PlusEthoxydiglycol  5.00 Tamibarotene#  0.50 # Adjustments can be made forconcentrations

Heat phases A and B separately to 75° C., add phase B to phase A, withstirring, and homogenize, adjust the pH to approx. 5.5-6.5 with phase C,successively add the components of phase D at approx. 65° C. andhomogenize. Successively add the components of phase Eat approx. 35° C.,cool to room temperature and, if necessary, readjust the pH to 5.0-5.5.

EXAMPLE 5 Testing of Tamibarotene

A study was conducted based upon the following references: OECD 404,Organization for Economic Co-Operation and Development (OECD),Guidelines for the Testing of Chemicals, “Acute DermalIrritation/Corrosion”, adopted 24 Apr. 2002. ISO 10993-12, 2012,Biological Evaluation of Medical Devices—Part 12: Sample Preparation andReference Materials. ISO/IEC 17025, 2005, General Requirements for theCompetence of Testing and Calibration Laboratories.

The skin of three albino rabbits was prepared for testing by clippingthe skin of the trunk free of hair at the application sites within 24hours of the test. The sites of application were not abradeddeliberately or accidentally during preparation. Tamibarotene wasadministered at dose levels of 0.02%, 0.04%, and 0.08% in 60% DMSO. Theanimals were treated by introducing each dose level (0.5 ml) under gauzepatches at individual application sites. The control (0.5 ml of 60%DMSO) was applied to a fourth site.

As it was suspected that tamibarotene might produce severeirritancy/corrosion, a single animal test was initially employed. Testpatches of each dose level and control were applied. After threeminutes, the skin sites were examined by gently lifting the bandage toexamine the skin without bandage removal. Since no serious skin reactionwas observed, the sites were examined in the same manner after one hour.The observation at this stage indicated that exposure could humanely beallowed to extend to four hours. If a corrosion effect was observedafter three minutes or one hour, the test was to be immediatelyterminated.

Because an irritation or corrosive effect was not observed in theinitial test after one hour, the response was confirmed using twoadditional animals dosed with each dose level and control at individualapplication sites for four hours. At the end of the exposure period, thewrapping was removed from and the skin washed with USP sterile Water forInjection (SWFI) to remove any test substance still remaining. The threeanimals were observed for signs of erythema and edema at 60 minutes, andthen at 24, 48, and 72 hours after bandage removal. Observations werescored according to the Draize Scale for Scoring Skin Reactions.

All animals gained weight. None of the test sites presented any signs oferythema or edema at any of the observation points. None of the controlsites of any animal at any of the observation periods showed signs oferythema or edema.

The test article was tested for its potential to produce primary dermalirritation after a single topical 4-hour application to the skin ofalbino rabbits. The test article was considered a non-irritant whentested at dose levels of 0.02%, 0.04%, and 0.08% in 60% DMSO.

Ammonium Lactate Compositions

Ammonium lactate is a moisturizing agent known in the art that istypically formulated as an oil in water emulsion for topicaladministration. Currently available products suffer from the (problemthat sufactants used to emulsify sunscreen agents also remove the agentsused to promote absorption from the skin when in the presence of water.This causes loss of UV absorbent activity and sun protectant effectssunscreen agents is lost.

The present invention solves the problem by using a new emulsificationtechnology based on Pemulen. This invention provides novel cosmeticcombination compositions of ammonium lactatehttp://www.drugs.com/ingredient/ammonium-(1), in a novel polymericemulsification technology using Acrylates/C10-30 Alkyl AcrylateCrosspolymer, (Pemulen™ TR-1 Polymeric Emulsifier). The Acrylates/C10-30Alkyl Acrylate Crosspolymer, is a versatile polymer which can emulsifyup to 30% oil by weight, within a pH range of 4-5.5, and up to 20% oilover the pH range of 3-11. Oil-in-water creams typically at 0.1 percentmethyl and propyl parabens are used at levels ranging from 0.01 to 0.3%and fragrance in an ternary sterically stabilized emulsion for topicalimprovement of skin appearance in normal and aged human skin. Like otheroil in water cosmetic emulsions, creams have traditionally beenemulsified with stearate or nonionic surfactants at 2%-6%. Inherent tosurfactant emulsification of UV absorbers is the propensity for thesurfactants to remove the absorbers from the skin when contacted bywater.

Pemulen TR1 is a polymeric emulsifier produced by Noveon. A blockcopolymer consisting of a poly acrylic acid similar to the Carbopolresins presently used to make aqueous and solvent gels in artconservation (Carbopol 934, Carbopol. 940, Carbopol 941) cross-linkedwith a long-chained methacrylate, this carbomer has a lipohipllicregions (the methacrylate) as well as hydrophilic regions (the acrylicacid). In the cosmetic industry literature, Pemulen TR-1 is part of aclass of copolymers are referred to as acrylate/C10-30 alkyl acrylatecross polymers (6), having the following structure:

See http://pemulentr2.pbworks.com/f/PemulenTR2.pdf

These regions of differing affinity allow Pemulen TR1 or TR2 to act as aprimary emulsifier, that is, it can be used to make oil in wateremulsions without the usual required addition of soap or surfactant.

Pemulen TR1 or TR2 docs not form emulsions in the same way thattraditional surfactants do. To produce oil in water emulsion, atraditional surfactant surrounds a droplet of oil to keep it suspendedin oil. Nonionic surfactants used for cleaning painted surfaces, asdescribed in Wolvers' Cleaning Painted Surfaces: Aqueous Methods, mightbe used in concentrations as high as 30% to form a macroemulsion

In contrast, Pemulen TR1 is said to form stable O/W emulsions with aslittle as 0.4%, binding to the oil droplets with the lipophilic portionsof the polymer chain that forms the gel.

Gels made with Pemulen TR-1 are most viscous in the pH range of 5-9. Arange of alkaline materials are suggested by the manufacturer toformulate aqueous gels using Pemulen TR-1, including sodium hydroxide,ammonium hydroxide, triethanolamine (TEA), and Ethameen C-25.

One interesting feature possessed by Pemulen is that this emulsifyingagent is designed to break when the gel is in contact with a saltconcentration similar to what one would find on human skin. This is adesirable in the cosmetics industry where moisturizers need to bequickly delivered and absorbed into the user's skin, but this may be aless desirable characteristic of an emulsion designed to clean works ofart. In practice, this breakage of the emulsion has been observed whenattempting to clean very grimy areas and allowing the gel to dwell foran extended period. Although the vast majority of cream or emulsionproducts in the marketplace contain water-insoluble actives, thesurfactants can re-emulsify the actives and cause wash-off, leaving theskin unprotected.

Those familiar with the art have countered this phenomenon byincorporating waxes or water resistant, film-forming polymers into theirformulations. Such a polymer forms an effective barrier, which preventsabsorber wash-off, but it may produce negative aesthetic effects such aslong rub-in times and a tacky or heavy feel on the skin. However, anovel combination of Ammonium Lactate and Pemulen® polymeric emulsifiersmeet the FDA definition of “water-proof” without the use of film-formingpolymers, waxes and the like. Because these emulsions contain verylittle or no surfactants, the water-insoluble UV absorbers remain on theskin, even after an 80 minute exposure to water. The triggered releaseof the oil phase upon product application ensures that the absorbers arefree to spread onto the epidermis where they arc immediately active (1).Ammonium lactate is the ammonium salt of lactic acid. This productspecially formulates ammonium lactate 20 wt. percent to provide a creampH of 4.5-6.5. It may also contain glycerin, isopropyl palmitate,dimethicone, ginko biloba, methyl paraben, propyl paraben or butylparabens fragrance and water.

The percentage of Ammonium lactate is preferably between about 17 toabout 20 percent. Optionally, the formulation comprises alpha-Bisabolol,an anti-irritant, and/or a retinoid, such as Tamibarotene, or atriterpinoid such as Betulen [473-98-3] C30H50O2, molecular mass 442,7and related compounds like betulin, lupeol, and betulinic acid.

EXAMPLE 6 Ternary Anti-Wrinkle Emulsion of 20 Weight Percent AmmoniumLactate

The formula is a ternary formulation consisting of three parts which areultimately combined to form a stable oil in water emulsion. The order ofaddition of the ingredients should be followed strictly as written inTable 4 and the description that follows. Otherwise, the ingredientsfall out of solution.

TABLE 4 Ingredient Percent Weight (g) Ternary Ingredient-Part 1 Order ofAddition Demineralized Water  63.1 155.5 Methyl Paraben  0.1  0.5 PropylParaben  0.1  0.5 Glycerin  2.0  10.0 Ammonium Lactate (20 wt. %)  8.0200.0 Total  73.3 366.5 Ternary Ingredient-Part 2 Order of AdditionDemineralized Water  18.0  90.0 Isopropyl Palmitate  2.5  12.5Dimethicone (Mw 30,000)  2.5  12.5 White Petrolatum  1.0  5.0 Ginkgo(Ginkgo biloba)  1.0  5.0 Total  25.0 125.0 Ternary Ingredients-Part 3Order of Addition Pemulen ® TR  1.5  7.5 Fragrance (Belle Air #7564) 0.2  1.0 Total  1.7  8.5 Total all 3 parts 100.0 500.0

A. Part 1

Part 1 is formed as follows:

-   a. Add Demineralized water to a 1000 ml beaker. Stirring or    Agitation at 600 rpm-   b. Add methyl paraben-   c. Add propyl paraben-   d. Add glycerin-   e. Add ammonium Lactate-   f. Increase stirring rate or agitation to 1500 rpm

B. Part 2

Part 2 is formed as follows:

-   i. Add demineralized water to an 800 ml beaker. Stir or Agitation at    600 rpm-   ii. Add Isopropyl palmitate-   iii. Add dimethicone-   iv. Add white petrolatum-   v. Add gingko biloba-   vi. Increase agitation or stirring 1500 rpm

Mix part 1 and part 2 for 30 minutes

-   a. Slow agitation or stirring down on part 1 to 600 rpm and blend    part 2 into part 1-   b. Increase agitation of the combined formulation to 1800 rpm for 30    minutes    c. Part 3

The final formulation is produced as follows:

-   a. Slow agitation of combined formulation to 600 rpm-   b. Add Pemulen® TR1 OR TR2 very slowly (all of it)-   c. Increase stirring speed to 1800 rpm for 30 minutes to disperse    all of Pemulen® TR1 OR TR2-   d. Increase agitation to 2800 rpm and hold until the emulsion is    smooth and creamy without any of the oils floating on the surface-   e. Slow agitation down to 600 rpm and add the fragrance-   f. Mix well and place in a proper container (jar or tubes)

EXAMPLE 7 Ternary Anti-Wrinkle Emulsion of 20 Weight PercentTamibarotene in Ammonium Lactate

A combination tamibarotene and ammonium lactate anti-wrinkle emulsioncan be prepared as shown below.

TABLE 5 Ingredient Percent Weight (g) Ternary Ingredient-Part 1 Order ofAddition 1. Demineralized Water  63.1 155.5 2. Methyl Paraben  0.1  0.53. Propyl Paraben  0.1  0.5 4. Glycerin  1.0  10.0 5. Ammonium Lactate(20 wt. %)  8.0 200.0 6. Tamibarotene (suspended in  0.05-1.0  1.8-3.51Ammonium Lactate §Total (adjusted according to  73.3 370.0 ActiveConcentrations) Ternary Ingredient-Part 2 Order of Addition 1.Demineralized Water  18.0  90.0 2. Isopropyl Palmitate  2.5  12.5 3.Dimethicone (Mw 30,000)  2.5  12.5 4. White Petrolatum  1.0  5.0 5.Ginkgo (Ginkgo biloba)  1.0  5.0 Total  25.0 125.0 TernaryIngredients-Part 3 Order of Addition 1. Pemulen ® TR  1.5  7.5 2.Fragrance (Belle Air #7564)  0.2  1.0 3. Total  1.7  8.5 Total all 3parts 100.0 500.0

A. Part 1.

The order of addition of the ingredients is listed just the way theformulation is written (through all stages). Otherwise, the ingredientsfall out of solution.

-   a. Add Demineralized water to a 1000 ml beaker. Stirring or    Agitation at 600 rpm-   b. Add methyl paraben-   c. Add propyl paraben-   d. Add glycerin-   e. Add ammonium Lactate-   f. Increase stirring rate or agitation to 1500 rpm

B. Part 2

-   a. Add demineralized water to an 800 ml beaker. Stir or Agitation at    600 rpm-   b. Add Isopropyl palmitate-   c. Add dimethicone-   d. Add white petrolatum-   e. Add gingko biloba-   f. Increase agitation or stirring 1500 rpm

C. Mix part 1 and part 2 for 30 minutes.

D. Slow agitation or stirring down on part 1 to 600 rpm and blend part 2into part 1.

E. Increase agitation of the combined formulation to 1800 rpm for 30minutes.

F. Part 3

-   -   1. Slow agitation of combined formulation to 600 rpm    -   2. Add Pemulen® TR1 OR TR2 very slowly (all of it)    -   3. Increase stirring speed to 1800 rpm for 30 minutes to        disperse all of Pemulen® TR1 OR TR2    -   4. Increase agitation to 2800 rpm and hold until the emulsion is        smooth and creamy without any of the oils floating on the        surface.    -   5. Slow agitation down to 600 rpm and add the fragrance    -   6. Mix well and place in a proper container (jar or tubes).

One of skill in the art will appreciate that substitutions anddeviations from the above formulation may be permissible withoutdeparting from the spirit of the invention as long as the changes to notbreak the emulsion. In particular the use of tinting agents and perfumesarc contemplated.

REFERENCES

-   -   1.        http://www.drugs.com/ingredient/ammouium-lactate.html{http:/pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=10586}    -   2.        http://www.lubrizol.com/PersonalCare/Products/Pemulen/PemulenTR-1.html    -   3.        http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=1201551&loc=cc_rcs    -   4. Y. Hamada. I. Yamada. M. Uenaka, T. Sakata, U.S. Pat. No.        5,214,202 (1993).

In one aspect of the invention, is a composition for reducing theeffects of aging comprising tamibarotene in a cosmetically acceptablecarrier. In one embodiment, the effects of aging are selected fromincrease in skin roughness, loss of skin elasticity, increase in skintransparency, skin fragility, increased frequency of bruising,macroscopic appearance of skin wrinkles and folds, and skindiscoloration. In one embodiment, the carrier is at least onepolyethylene glycol (PEG) of cosmetically acceptable grade. In oneembodiment, the polyethylene glycol is a mixture of PEG 300 and PEG1540. In another embodiment, the tamibarotene is dissolved in PEG 300and added to melted PEG 1540. In one embodiment, the composition furthercomprises an anti-irritant. In one embodiment, the anti-irritant is(-)-α-Bisabolol. In another embodiment, the composition comprises anantioxidant. In one embodiment, the anti-oxidant is butylatedhydroxytoluene (BHT). In another embodiment, the composition is stableat room temperature.

In another aspect of the invention is a topical formulation oftamibarotene co-formulated with ammonium lactate in an acrylates/C10-30alkyl acrylate crosspolymer. In one embodiment, the topical formulationis a formulation that is a sterically stabilized oil in water (o/w)emulsion. In another embodiment, the ammonium lactate is present fromabout 17 to about 20 percent by weight, in another embodiment, thecomposition further comprises an anti-irritant and/or a retinoid. In oneembodiment, the anti-irritant is (-)-α-Bisabolol.

In another aspect of the invention is a ternary formulation oftamibarotene comprising:

-   -   a. a first part comprising tamibarotene dissolved in at least        one paraben, water, and glycerin;    -   b. a second part comprising water, an emollient, a siloxane, and        petrolatum; and    -   c. a third part comprising the first and second parts together        with an acrylates/C10-30 alkyl acrylate crosspolymer.

In one embodiment, the ternary formulation comprises an additionalcosmetic agent.

In another embodiment, the ternary formulation is a formulation inwhich:

-   -   a. the first part comprises demineralized water, methyl paraben,        propyl paraben, glycerin, and tamibarotene;    -   b. the second part comprises demineralized water, isopropyl        palmitate, dimethicone, white petrolatum, gingko biloba; and    -   c. the third part comprises parts one and two together with        Pemulen™.

In another aspect of the invention is a method of making a ternaryformulation of tamibarotene comprising:

-   -   a. forming a first part:        -   i. adding demineralized water to a 1000 ml beaker;        -   ii. stirring or agitation at 600 rpm;        -   iii. adding methyl paraben;        -   iv. adding propyl paraben;        -   v. adding glycerin;        -   vi. adding tamibarotene;        -   vii. increasing stirring rate or agitation to 1500 rpm;    -   b. forming a second part by:        -   i. adding demineralized water to an 800 ml beaker;        -   ii. stirring or agitating at 600 rpm;        -   iii. adding isopropyl palmitate;        -   iv. adding dimethicone;        -   v. adding white petrolatum;        -   vi. adding gingko biloba:        -   vii. increasing agitation or stirring to 1500;        -   viii. mix part 1 and part 2 for 30 minutes;            -   1. slow agitation or stirring down on part 1 to 600 rpm                and blend part 2 into part 1;            -   2. increase agitation of the combined formulation to                1800 rpm for 30 minutes:    -   c. forming a third part by:        -   i. slow agitation of combined formulation of the second part            to 600 rpm;        -   ii. adding Pemulen™ TR-1 or TR-2 very slowly;        -   iii. increasing stirring speed to 1800 rpm for 30 minutes to            disperse all of Pemulen™® TR-1 or TR-2;        -   iv. increasing agitation to 2800 rpm and until the emulsion            is smooth and creamy without any of the oils floating on the            surface;        -   v. slowing agitation down to 600 rpm and adding a fragrance;            and        -   vi. mixing well and placing in a proper vessel.

In another embodiment is a topical formulation of ammonium lactate in anacrylates/C10-30 alkyl acrylate crosspolymer. In one embodiment, theformulation is an oil in water (o/w) emulsion. In one embodiment of thetopical formulation, the ammonium lactate is present from about 17 toabout 20 percent by weight. In another embodiment, the topicalformulation comprises an anti-irritant, and or a retinoid. In oneembodiment, the anti-irritant is (-)-α-Bisabolol and the retinoid istamibarotene.

In another embodiment is a method of making a ternary formulation ofammonium lactate comprising:

-   -   a. forming a first part by:        -   i. adding demineralized water to a 1000 ml beaker;        -   ii. stirring or agitating at 600 rpm;        -   iii. adding methyl paraben;        -   iv. adding propyl paraben:        -   v. adding glycerin;        -   vi. adding ammonium lactate.        -   vii. increasing stirring rate or agitating to 1500 rpm:            forming a second part:        -   i. adding demineralized water to an 800 ml beaker;        -   ii. stirring or agitating at 600 rpm;        -   iii. adding isopropyl palmitate;        -   iv. adding dimethicone;        -   v. adding white petrolatum;        -   vi. adding gingko biloba;        -   vii. increasing stirring rate or agitating to 1500 rpm;        -   viii. mixing part 1 and part 2 for 30 minutes;        -   ix. slowly agitating or stirring down part 1 to 600 rpm and            blend part 2 into part 1;        -   x. increasing the agitation or the stirring rate of the            combined formulation to 1800 rpm for 30 minutes;    -   c. forming a third part by:        -   i. slow agitation or stirring of combined formulation of the            second part to 600 rpm;        -   ii. adding Pemulen™® TR-1 or TR-2 very slowly (all of it);        -   iii. increasing stirring rate to 1800 rpm for 30 minutes to            disperse all of Pemulen™® TR-1 or TR-2;        -   iv. increasing agitation to 2800 rpm and hold until the            emulsion is smooth and creamy without any of the oils            floating on the surface;        -   v. slowing agitation down to 600 rpm and adding fragrance;            and        -   vi. mixing well and placing in a proper container (jar or            tubes).

1-25. (canceled)
 26. A topical composition for reducing the effects ofaging comprising tamibarotene in a cosmetically acceptable carrier,wherein the carrier comprises an emulsifier of an acrylates/C10-30 alkylacrylate crosspolymer.
 27. The topical composition of claim 26, whereinthe carrier comprises a stable oil in water emulsion.
 28. The topicalcomposition of claim 26, wherein the effects of aging are selected fromincrease in skin roughness, loss of skin elasticity, increase in skintransparency, skin fragility, increased frequency of bruising,macroscopic appearance of skin wrinkles and folds, and skindiscoloration.
 29. The topical composition of claim 26, wherein theacrylates/C10-30 alkyl acrylate crosspolymer is a Pemulen™ emulsifier.30. The topical composition of claim 29, wherein the Pemulen™ emulsifieris Pemulen™ TR-1 or Pemulen™ TR-2.
 31. The topical composition of claim26, wherein the composition further comprises ammonium lactate.
 32. Thetopical composition of claim 31, wherein the ammonium lactate is presentin the composition in an amount between about 17 to 20 weight percent.33. The topical composition of claim 26, wherein the composition is acream.
 34. The topical composition of claim 26, wherein the compositionis a gel.
 35. A method for reducing the effects of aging comprising:applying to the skin a topical formulation of tamibarotene in acosmetically acceptable carrier, wherein the carrier comprises anemulsifier of an acrylates/C10-30 alkyl acrylate crosspolymer.
 36. Themethod of claim 35, wherein the carrier comprises a stable oil in wateremulsion.
 37. The method of claim 35, wherein the effects of aging areselected from increase in skin roughness, loss of skin elasticity,increase in skin transparency, skin fragility, increased frequency ofbruising, macroscopic appearance of skin wrinkles and folds, and skindiscoloration.
 38. The method of claim 35, wherein the acrylates/C10-30alkyl acrylate crosspolymer is a Pemulen™ emulsifier.
 39. The method ofclaim 38, wherein the Pemulen™ emulsifier is Pemulen™ TR-1 or Pemulen™TR-2.
 40. The method of claim 35, wherein the composition furthercomprises ammonium lactate.
 41. The method of claim 40, wherein theammonium lactate is present in the composition in an amount betweenabout 17 to 20 weight percent.
 42. The method of claim 35, wherein thecomposition is a cream.
 43. The method of claim 35, wherein thecomposition is a gel.
 44. A topical composition comprising tamibarotenein a cosmetically acceptable carrier, wherein the carrier comprises anemulsifier of an acrylates/C10-30 alkyl acrylate crosspolymer.
 45. Thetopical composition of claim 44, wherein the carrier comprises a stableoil in water emulsion.
 46. The topical composition of claim 44, whereinthe topical composition reduces acne.
 47. The method of claim 44,wherein the method treats eczema, psoriasis, wrinkles or dry skin. 48.The topical composition of claim 44, wherein the acrylates/C10-30 alkylacrylate crosspolymer is a Pemulen™ emulsifier.
 49. The topicalcomposition of claim 48, wherein the Pemulen™ emulsifier is Pemulen™TR-1 or Pemulen™ TR-2.
 50. The composition of claim 44, wherein thecomposition further comprises ammonium lactate.
 51. The composition ofclaim 50, wherein the ammonium lactate is present in the composition inan amount between about 17 to 20 weight percent.
 52. The composition ofclaim 44, wherein the composition is a cream.
 53. The composition ofclaim 44, wherein the composition is a gel.
 54. A method for treatingskin comprising: applying to the skin a topical formulation oftamibarotene in a cosmetically acceptable carrier, wherein the carriercomprises an emulsifier of an acrylates/C10-30 alkyl acrylatecrosspolymer.
 55. The topical composition of claim 54, wherein thecarrier comprises a stable oil in water emulsion.
 56. The method ofclaim 54, wherein the method reduces acne.
 57. The method of claim 54,wherein the method treats eczema, psoriasis, wrinkles, or dry skin. 58.The method of claim 54, wherein the acrylates/C10-30 alkyl acrylatecrosspolymer is a Pemulen™ emulsifier.
 59. The method of claim 58,wherein the Pemulen™ emulsifier is Pemulen™ TR-1 or Pemulen™ TR-2. 60.The method of claim 54, wherein the composition further comprisesammonium lactate.
 61. The method of claim 60, wherein the ammoniumlactate is present in the composition in an amount between about 17 to20 weight percent.
 62. The method of claim 54, wherein the compositionis a cream.
 63. The method of claim 54, wherein the composition is agel.
 64. A topical formulation of ammonium lactate in a carriercomprising an acrylates/C10-30 alkyl acrylate crosspolymer.
 65. Thetopical formulation of claim 64, wherein the formulation is oil in water(o/w) emulsion.
 66. The topical formulation of claim 64, wherein theammonium lactate is present from about 17 to about 20 percent by weight.67. The topical formulation of claim 64, wherein the formulation furthercomprises an anti-irritant and/or a retinoid.